TY  - JOUR
AU  - Peralta Reyes, Fernanda S.
AU  - Sommerhage, Simon
AU  - Willbold, Dieter
AU  - Schröder, Gunnar F.
AU  - Gremer, Lothar
TI  - Lecanemab Binds to Transgenic Mouse Model‐Derived Amyloid‐β Fibril Structures Resembling Alzheimer's Disease Type I, Type II and Arctic Folds
JO  - Neuropathology & applied neurobiology
VL  - 51
IS  - 3
SN  - 0305-1846
CY  - Oxford [u.a.]
PB  - Wiley-Blackwell
M1  - FZJ-2025-03033
SP  - e70022
PY  - 2025
AB  - Aims:Lecanemab, an Alzheimer’s disease US Food and Drug Administration-approved monoclonal antibody, was previously reported to have a high affinity against intermediately sized amyloid-β aggregates. Subsequently, it was observed by immunogold labelling that lecanemab can also bind to human type I amyloid-β fibrils. To determine whether lecanemab binds to amyloid-β fibril structures other than type I, we analysed its binding capacity to various structurally defined and pathologically relevant amyloid-β fibrils.Methods:We performed immunogold labelling with lecanemab on extracted amyloid-β fibril preparations from six different Alzheimer´s disease mouse models whose structures were previously solved by cryo-EM and quantified the relative binding affinities of lecanemab to the different fibril polymorphs.Results:Our results show that lecanemab exhibits high binding affinity to amyloid-β fibril structures that have a flexible N-terminus in common, as is the case for type I, type II and murine type III amyloid-β fibril polymorphs, which resemble or are identical to human structures observed in sporadic and familial cases of Alzheimer’s disease, including a case with the Arctic (E22G) mutation. In contrast, only weak lecanemab binding was observed for murine amyloid-β fibrils with a fixed and ordered N-terminus.Conclusions:These findings may also explain the low incidence of ARIA-E with lecanemab in clinical trials. This is because human meningeal amyloid-β fibrils derived from cerebral amyloid angiopathy affected brain tissue also contain a fixed and ordered N-terminus, most likely preventing lecanemab binding.
LB  - PUB:(DE-HGF)16
C6  - 40495448
UR  - <Go to ISI:>//WOS:001507890600001
DO  - DOI:10.1111/nan.70022
UR  - https://juser.fz-juelich.de/record/1044126
ER  -